Lena Mary Calhoun Horne was born on June 30, 1917, in Bedford-Stuyvesant, Brooklyn, to Edwin and Edna Horne, into the well-educated upper stratum of Black New York. Her father, a gambler and onetime hotel and restaurant owner, left the family when she was three and settled in Pittsburgh's Hill District; her mother, an actress with a Black theater troupe, traveled widely, and Horne was raised mainly by her paternal grandparents. At five she was sent to Georgia, and from 1927 to 1929 she lived at Fort Valley with her uncle Frank S. Horne, a college dean. Back in New York at twelve, she attended St. Peter Claver School and then Girls High School in Brooklyn, which she left at sixteen. In the fall of 1933 she joined the chorus line of the Cotton Club in Harlem, where the performers were Black and the audience was white only, and in the spring of 1934 she had a featured spot in the Cotton Club Parade starring Adelaide Hall, who took her under her wing. Her first screen appearance was as a dancer in the short Cab Calloway's Jitterbug Party (1935), and during years spent with her father in Pittsburgh she learned music from, among others, Billy Strayhorn and Billy Eckstine. She married Louis Jordan Jones there in January 1937.

Her first records came as a band singer. She toured with Noble Sissle's orchestra, billed as Helena Horne, and sang "That's What Love Did to Me" and "I Take to You" at his Decca session in New York on March 11, 1936. After separating from her husband she toured in 1940 and 1941 with Charlie Barnet's band, which recorded four sides with her for Victor on January 7 and 23, 1941, among them "Good-for-Nothin' Joe," "You're My Thrill," and "Haunted Town." She disliked life on the road and left to work at Café Society, New York's first integrated nightclub, where she worked with Paul Robeson. She replaced Dinah Shore on NBC's jazz series The Chamber Music Society of Lower Basin Street, which led to Victor records with the program's Dixieland group under Henry Levine on June 23 and 25, 1941 ("St. Louis Blues," "Careless Love," "Aunt Hagar's Blues," and "Beale Street Blues"). The next day she cut "Love Me a Little Little" and "Don't Take Your Love from Me" with Artie Shaw's orchestra, and on September 16, 1941 she recorded "Out of Nowhere" and "Prisoner of Love" for Columbia with Teddy Wilson's orchestra. Her own Victor sides of December 15 to 17, 1941, arranged and conducted by Lou Bring, included "Stormy Weather," issued in 1942, which reached number 21 on the US popularity chart. In 1945 and 1946 she sang with Billy Eckstine's orchestra, and in the same years she recorded with Horace Henderson's orchestra and the Phil Moore Four.

In January 1942 she made her Hollywood nightclub debut at the Little Troc on the Sunset Strip, and a few weeks later MGM signed her. She made her MGM debut in Panama Hattie (1942), sang the title song of Stormy Weather (1943) on loan to 20th Century Fox in a film that also featured Fats Waller and Cab Calloway, and appeared in Cabin in the Sky (1943). Because her scenes had to be removable for cities where theaters would not show films with Black performers, most of her film work consisted of stand-alone musical numbers, and she became the first African-American elected to the Screen Actors Guild board. In December 1947 she married Lennie Hayton in Paris. Hayton, MGM's music director, had been a pianist in Paul Whiteman's orchestra, where he played alongside Bix Beiderbecke and Frankie Trumbauer, and he became her conductor and arranger. She was blacklisted in the 1950s for her 1940s associations with communist-backed groups, which she later disavowed. After Duchess of Idaho (1950) and Meet Me in Las Vegas (1956) she made few films, saying she was tired of the typecast role of standing against a pillar to sing a song.

As a nightclub headliner she played the Sands in Las Vegas, the Cocoanut Grove in Los Angeles, and the Waldorf-Astoria in New York. Her first complete LP for RCA Victor was It's Love (1955). Lena Horne at the Waldorf Astoria, recorded on the evening of December 31, 1956 and issued in 1957, was one of the first non-classical live albums made in stereo, peaked at number 24 on the Billboard album chart, and became the best-selling record by a female artist in RCA Victor's history up to that time. Hayton arranged and conducted her studio albums Stormy Weather (1957), Give the Lady What She Wants (1958, number 20), and Songs by Burke and Van Heusen (1959), the last two with Ralph Burns also credited as arranger. In 1957 she starred on Broadway in the Caribbean-flavored musical Jamaica, with Adelaide Hall in the cast at her request, and became the first African-American woman nominated for a Tony Award for best actress in a musical. Porgy and Bess (1959), a set of Gershwin songs with Harry Belafonte, reached number 13. Her 1962 album Lena...Lovely and Alive paired her with Marty Paich's arrangements and a Los Angeles band that included drummer Shelly Manne, trumpeters Jack Sheldon and Pete Candoli, trombonist Frank Rosolino, saxophonists Bill Perkins and Joe Maini, and pianist Gene DiNovi; it earned a Grammy nomination.

Horne's activism ran alongside the music. In 1941 she worked with Paul Robeson at Café Society, and she later worked with Eleanor Roosevelt on anti-lynching legislation, appeared at an NAACP rally in Jackson, Mississippi, with Medgar Evers the weekend before his assassination, and spoke and sang at the March on Washington in August 1963 on behalf of the NAACP, SNCC, and the National Council of Negro Women. The NAACP awarded her its Spingarn Medal in 1983.

Her recordings after 1965 leaned toward pop and soul, with some jazz-world collaborators. Lena & Gabor (1970, Skye) paired her with guitarist Gábor Szabó in arrangements by Gary McFarland, with Cornell Dupree and Eric Gale among the guitarists, and Lena & Michel (1975, RCA) was arranged by Michel Legrand, with Ron Carter on bass and Thad Jones among the trumpeters. A 1973 television special with Tony Bennett led to a joint tour of the United States and Britain, and the 1976 album Lena: A New Album, arranged by Robert Farnon, includes Phil Woods on saxophone. She announced her retirement in March 1980, but on May 12, 1981, she opened Lena Horne: The Lady and Her Music at the Nederlander Theatre in New York. The one-woman show ran 333 performances until June 30, 1982, her 65th birthday, then toured 41 cities in the United States and Canada through June 17, 1984 before playing London and Stockholm. It earned her a Special Tony Award, and its cast album, produced by Quincy Jones for his Qwest label, won two Grammys. A 1983 duet project with Frank Sinatra, to be produced by Jones, was abandoned.

Her 1988 studio album The Men in My Life included duets with Joe Williams and Sammy Davis Jr., and in 1989 she received the Grammy Lifetime Achievement Award. In the 1990s she recorded for Blue Note. We'll Be Together Again (1994), a Grammy nominee, includes four songs by Strayhorn and one he wrote with Duke Ellington, with Toots Thielemans on harmonica and Jerome Richardson on tenor saxophone. An Evening with Lena Horne (1995), recorded live at the Supper Club in New York in September 1994 with Mike Renzi's rhythm section and members of the Count Basie Orchestra, won the Grammy for Best Jazz Vocal Performance. Being Myself (1998), her last studio album, features George Benson, Milt Jackson, and Donald Harrison. Her voice is also on Simon Rattle's Classic Ellington (2000). She withdrew from public life in 2000, and Seasons of a Life (2006), outtakes assembled by her guitarist and music director Rodney Jones, has Herbie Hancock on piano on two tracks.

Horne died of congestive heart failure in New York City on May 9, 2010, at the age of 92. Her honors include the Kennedy Center Honors (1984), the Grammy Lifetime Achievement Award (1989), and an NAACP Image Award for Outstanding Jazz Artist (1999). In 2021 the bandshell in Brooklyn's Prospect Park was renamed the Lena Horne Bandshell, and in 2022 the Brooks Atkinson Theatre on Broadway became the Lena Horne Theatre, the first Broadway house named for a Black woman.

Horne was not only a jazz singer. English Wikipedia describes her first as a singer, actress, dancer, and civil rights activist and lists her genres as R&B, soul, Broadway, traditional pop, and vocal jazz; the MGM musicals, Jamaica, the pop and soul albums of the late 1960s and 1970s, and the Broadway one-woman show all sit largely outside jazz. Her jazz credentials are nonetheless documented. She sang with the orchestras of Noble Sissle, Charlie Barnet, Artie Shaw, Teddy Wilson, and Billy Eckstine, and with Henry Levine's Dixieland group on radio and record, and her Victor and Columbia sides of 1941 are filed as jazz and dance band recordings with a female vocal. Billy Strayhorn, a Pittsburgh teacher of her youth, remained what Wikipedia calls an important professional mentor who helped her singing technique; she recorded his "You're the One" on It's Love (1955), "Maybe" on Lena Horne at the Sands (1961), and four of his songs on We'll Be Together Again (1994). Her Waldorf-Astoria set mixed Cole Porter and Broadway material with a Duke Ellington medley and a Fats Waller standard, "Honeysuckle Rose." In the 1990s she recorded for Blue Note, won the Grammy for Best Jazz Vocal Performance, was nominated in the jazz vocal category for The Men in My Life (1988), and received the NAACP Image Award for Outstanding Jazz Artist. Her studio style was shaped by the arrangers around her: Lennie Hayton's orchestral settings in the 1950s, the Marty Paich band in 1962, and in the 1990s small groups led by pianist Mike Renzi. Billboard called the 1957 Stormy Weather a powerful package with a smartly sexy delivery, and AllMusic's review of Lena & Gabor heard a soulful sass missing from her earlier albums. Nancy Wilson's profile lists Horne as a model for her overall look.